Anti-Inflammatory Lipid Mediators in Asthma

 描述（由申请人提供）：由还原-氧化（氧化还原）依赖性翻译后修饰介导的细胞信号传导作用包括半胱氨酸的氧化、谷胱甘肽化、S-亚硝化和烷基化。这些反应将代谢和炎症状态与细胞和器官功能的变化密切联系起来，因为介导代谢和炎症反应的许多酶、受体和转录调节蛋白含有功能显著的高活性半胱氨酸硫醇。特别关注的是由一氧化氮（NO），亚硝酸盐（NO2-）和硝酸盐（NO3-）和二次氮氧化物介导的反应，以及它们通过脂肪酸硝化反应诱导的独特氧化还原信号反应。内源性产生的各种氮氧化物的性质和数量取决于炎症状态、饮食、酸性微环境和NO3-还原进入唾液细菌群体。许多这些产品是化学反应性的，并产生蛋白质NO-家庭复合物，蛋白质Cys-NO加合物（RSNO），并在研究计划中，亲电脂肪酸硝基烯烃（NO2-FA），容易和可逆地烷基化敏感的蛋白质硫醇。NO2-FAs的cGMP非依赖性多效性信号传导作用诱导适应性组织反应，包括脂肪因子和细胞因子表达的有益转变、胰岛素敏感性的恢复和气道过度活跃的减弱。这促使我们假设硝基脂肪酸信号的促进加重了代谢综合征诱导的高血压及其肺部并发症。为了测试这一概念，将通过进行机械揭示模型系统研究和盲法交叉设计2期临床研究来评估降低风险的药物策略：目的#1 -鉴定具有气道活动过度的肥胖小鼠的肺组织中NO2-FA内收的位点，并定义对口服NO2-FA施用的生化和生理反应。目的#2 -评价肥胖哮喘患者对口服给予的NO2-FA、10-硝基-十八碳-9-烯酸（NO2-OA）的临床反应。我们将确定NO2-FA诱导的PTMs的关键网站在肥胖小鼠的肺与气道多动（AHR），并确定这如何影响氧化还原敏感性转录因子（TF）的功能，基因表达谱和关键酶的活性靶标。目前的数据支持NO2-FA介导的PTM促进肺部炎症和AHR小鼠模型的有益反应。NO2-FA的IV和口服制剂都经过了广泛的临床前毒理学和药代动力学评价，并正在进行FDA批准的人体I期试验。肥胖哮喘患者对NO2-FA的生理和生化反应将在盲法、安慰剂对照的交叉研究中进行研究。预计对NO2-FA的这些反应比许多单靶点哮喘药物更有效，因为NO2-FA的多效性抗炎信号传导作用预计将在这种复杂的炎症表型中引起药理学共鸣，而不是音符。

 DESCRIPTION (provided by applicant): Cell signaling actions mediated by reduction-oxidation (redox)-dependent post-translational modifications include the oxidation, glutathionylation, S-nitrosation, and alkylation of cysteine. These reactions intimately link metabolic and inflammatory status with changes in cell and organ function, since many enzymes, receptors and transcriptional regulatory proteins mediating metabolic and inflammatory responses contain functionally- significant hyperactive cysteine thiols. Particular focus is being placed on reaction mediated by nitric oxide (NO), nitrite (NO2-) and nitrate (NO3-) and secondary nitrogen oxides and the unique redox signaling responses they induce via fatty acid nitration reactions. The nature and amounts of various nitrogen oxides generated endogenously are dependent on inflammatory status, diet, acidic microenvironments and NO3--reducing enter salivary bacterial populations. Many of these products are chemically-reactive and generate protein NO- home complexes, protein Cys-NO adducts (RSNO) and in the research plan, electrophilic fatty acid nitroalkenes (NO2-FA) that readily and reversibly alkylate susceptible protein thiols. The cGMP-independent pleiotropic signaling actions of NO2-FAs induce adaptive tissue responses that include beneficial shifts in adipokine and cytokine expression, restoration of insulin sensitivity and the attenuation of airway hyperactivity. This motivated us to hypothesize that the promotion of nitro-fatty acid signaling alleviates metabolic syndrome-induced hypertension and its pulmonary complications. To test this concept, a de- risked drug strategy will be evaluated by pursuing both mechanistically-revealing model system studies and a blinded crossover design Phase 2 clinical study: Aim #1 - Identify the sites of NO2-FA adduction in the lung tissue of obese mice with airway hyperactivity and define the biochemical and physiological responses to oral NO2-FA administration. Aim #2 - Evaluate the clinical responses of obese asthmatic patients to the orally-administered NO2-FA, 10-nitro-octadeca-9-enoic acid (NO2-OA). We will identify key sites of NO2-FA-induced PTMs in the lungs of obese mice with airway hyperactivity (AHR) and define how this affects redox-sensitive transcription factor (TF) function, gene expression profiles and activities of critical enzyme targets. Current data support that NO2-FA-mediated PTMs promote salutary responses in murine models of pulmonary inflammation and AHR. Both IV and oral formulations of NO2-FA have undergone extensive preclinical toxicology and pharmacokinetics evaluation and are in FDA-approved Phase 1 testing in humans. The physiological and biochemical responses of obese asthmatics to NO2-FA will be studied in a blinded, placebo-controlled crossover study. These responses to NO2-FA are anticipated to be more efficacious than many single-target asthma drugs, because the pleiotropic anti-inflammatory signaling actions of NO2-FA are expected to strike a pharmacological chord, rather than a note, in this complex inflammatory phenotype.